The ErbB2 receptor tyrosine kinase plays a critical role in a variety of developmental processes, and its aberrant activation may contribute to the progression of some breast and ovarian tumors. ASGP2, a transmembrane glycoprotein found on the surface of the highly metastatic ascites 13762 rat mammary adenocarcinoma cell line, is constitutively associated with ErbB2 in these cells and in mammary tissue from pregnant rats. Expression studies indicate that ASGP2 interacts directly and specifically with ErbB2 through one of its epidermal growth factor-like domains and that the co-expression of the two proteins in the same cell dramatically facilitates their direct stable interaction. Ectopic expression of ASGP2 in human melanoma tumor cells potentiates the response of endogenous ErbB2 to the neuregulin-1 growth factor. These observations point to a novel intramembrane mechanism for the modulation of receptor tyrosine kinase activity.ErbB2 (also known as Neu) is a 185-kDa cell surface transmembrane receptor tyrosine kinase that mediates the growth or differentiation of a variety of cultured cells and contributes to the proper development of cardiac and neural tissues during gestation (1-4). Its overexpression in numerous human tumors, including breast and ovarian tumors, correlates with earlier patient relapse and poor prognosis (5, 6). The observation that ErbB2 overexpression stimulates its protein-tyrosine kinase activity (7), together with the observation that activated alleles of the erbB2 gene induce metastatic tumors when expressed in murine mammary epithelium (8), suggest that the activation of ErbB2 kinase activity may play an important role in tumorigenesis or tumor progression.The protein-tyrosine kinase activity of ErbB2 may be activated by several soluble, diffusible ligands that possess epidermal growth factor (EGF) 1 -like domains. For example, EGF, transforming growth factor-␣, and amphiregulin are all capable of stimulating ErbB2 activity by binding to the related EGF receptor and promoting its heterodimerization with ErbB2 (9, 10). Likewise, the neuregulins (NRGs) bind to the ErbB3 and ErbB4 receptors and stimulate ErbB2 activity through receptor heterodimerization mechanisms (11,12). However, no molecularly characterized diffusible ligand has been demonstrated to act on ErbB2 directly, and it has been suggested that the primary function of this protein is to augment signaling through the ErbB receptor network by acting as an auxiliary co-receptor (13)(14)(15). In this context factors that influence the activity or availability of ErbB2 could have a significant impact on the strength or specificity of signaling and ultimately the cellular response. Strong candidates for such factors are cell surface proteins that possess EGF-like domains.The autonomously proliferating and highly metastatic rat ascites 13762 mammary adenocarcinoma cell line expresses a large sialomucin complex in abundance at its cell surface. This complex consists of two noncovalently associated proteins, ASGP1 and ASGP2, which ari...
MUC1 and MUC4 are the two membrane mucins that have been best characterized. Although they have superficially similar structures and have both been shown to provide steric protection of epithelial surfaces, recent studies have also implicated them in cellular signaling. They act by substantially different mechanisms, MUC4 as a receptor ligand and MUC1 as a docking protein for signaling molecules. MUC4 is a novel intramembrane ligand for the receptor tyrosine kinase ErbB2/HER2/Neu, triggering a specific phosphorylation of the ErbB2 in the absence of other ErbB ligands and potentiating phosphorylation and signaling through the ErbB2/ErbB3 heterodimeric receptor complex formed in the presence of neuregulin. In contrast, MUC1 has a highly conserved cytoplasmic tail, which binds beta-catenin, a key component of adherens junctions and a regulator of transcription, in a process that is tightly regulated by MUC1 phosphorylation. The specific localization of these membrane mucins to the apical surfaces of epithelial cells suggests that their signaling functions may be important as sensor mechanisms in response to invasion or damage of epithelia.
Sialomucin complex (SMC) is a large, heterodimeric glycoprotein complex composed of mucin (ASGP-1) and transmembrane (ASGP-2) subunits and expressed abundantly on the cell surface of ascites 13762 rat mammary adenocarcinoma cells. We have isolated recombinant cDNAs containing different numbers of ASGP-1 mucin repeats, which can be expressed as protein products with variable lengths. To study the anti-adhesive effect of SMC, these cDNAs were transfected into human cancer cell lines. Using a tetracycline-responsive, inducible expression system, we demonstrated that the overexpression of SMC induces morphology changes, cell detachment, and cell-cell dissociation of transfected A375 human melanoma cells in culture. The transition between the adherent and suspension states of the cells is fully reversible and dependent on the SMC expression level. The anti-adhesion effect of SMC was further analyzed kinetically by measuring the cell adhesion of transfected A375 melanoma and MCF-7 breast cancer cell lines to fibronectin, laminin, and collagen IV, demonstrating that SMC disrupts integrin-mediated cell adhesion to extracellular matrix proteins. The degree of this anti-adhesion effect was dependent on the number of mucin repeats in the SMC molecule as well as the level of cell surface expression.
Muc4/sialomucin complex (SMC) is a multifunctional glycoprotein complex which can repress apoptosis in transfected tumor cells. Its transmembrane subunit acts as an intramembrane ligand for the receptor tyrosine kinase ErbB2 to induce the phosphorylation of ErbB2 and, by acting synergistically with the ErbB3 ligand neuregulin, can potentiate the phosphorylation of ErbB2 and ErbB3. In the present study we show that Muc4/ SMC alone robustly induces the phosphorylation of ErbB2 to enhance the tyrosine phosphate epitope (Tyr1248) recognized by anti-phospho-ErbB2. Although this tyrosine phosphorylation has been implicated in cell transformation, it does not activate any of the three mitogen-activated protein kinases (MAPKs) or protein kinase B/Akt of the phosphatidyl inositol 3-kinase pathway. Instead, Muc4/SMC expression induces upregulation of the cell cycle inhibitor p27 kip , consistent with the expression of Muc4/SMC in differentiated, rather than proliferative, epithelial cells. Interestingly, a combination of Muc4/SMC and neuregulin downregulate p27 kip and activate protein kinase B/Akt. These observations suggest that Muc4/SMC acts as a regulator of differentiation by inducing a limited phosphorylation of ErbB2 and a modulator of proliferation when acting synergistically with neuregulin to induce a more extensive phosphorylation on both ErbB2 and ErbB3.
Overexpression of the membrane mucin MUC4/Sialomucin complex (SMC) has been observed during malignant progression of mammary tumors in both humans and rats, suggesting that deregulation of MUC4/SMC expression might facilitate development of these malignancies. As previously reported, overexpression of SMC results in suppression of both cell adhesion and immune killing of tumor cells. SMC also acts as a ligand for ErbB2/Neu, modulating phosphorylation of the receptor tyrosine kinase in the presence and absence of heregulin. The present studies investigated the e ect of Muc4/SMC up-regulation on primary tumor growth using a tetracycline-inducible SMC expression system in a xenotransplanted tumor model. SMC upregulation provoked rapid growth of transfected A375 melanoma in nude mice. Up-regulation of SMC, however, did not signi®cantly increase proliferation of A375 cells in vitro. Instead, a strong suppression of apoptosis was observed in situ in SMC-overexpressing tumors. These data suggest that Muc4/SMC expression promotes tumor growth in vivo at least in part via suppression of tumor cell apoptosis. Importantly, reduction of apoptosis was also observed in vitro, indicating that anti-apoptotic e ect of SMC is independent of tumor-host interactions. These ®ndings strongly suggest that SMC up-regulation alters intracellular signaling to favor cell survival, providing for the ®rst time evidence for the regulation of programmed cell death by a gene of the MUC family. Oncogene (2001) 20, 461 ± 470.
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